A Pooled Analysis of the EXAMINATION (clinical Evaluation of the Xience-V stent in Acute Myocardial INfArcTION) and COMFORTABLE-AMI (Comparison of Biolimus Eluted From an Erodible Stent Coating With Bare Metal Stents in Acute ST-Elevation Myocardial Infarction) Trials

Abstract

Objectives This study sought to study the efficacy and safety of newer-generation drug-eluting stents (DES) compared with bare-metal stents (BMS) in an appropriately powered population of patients with ST-segment elevation myocardial infarction (STEMI).

Background Among patients with STEMI, early generation DES improved efficacy but not safety compared with BMS. Newer-generation DES, everolimus-eluting stents, and biolimus A9-eluting stents, have been shown to improve clinical outcomes compared with early generation DES.

Methods Individual patient data for 2,665 STEMI patients enrolled in 2 large-scale randomized clinical trials comparing newer-generation DES with BMS were pooled: 1,326 patients received a newer-generation DES (everolimus-eluting stent or biolimus A9-eluting stent), whereas the remaining 1,329 patients received a BMS. Random-effects models were used to assess differences between the 2 groups for the device-oriented composite endpoint of cardiac death, target-vessel reinfarction, and target-lesion revascularization and the patient-oriented composite endpoint of all-cause death, any infarction, and any revascularization at 1 year.

Conclusions Among patients with STEMI, newer-generation DES improve safety and efficacy compared with BMS throughout 1 year. It remains to be determined whether the differences in favor of newer-generation DES are sustained during long-term follow-up.

Early generation drug-eluting stents (DES), namely, sirolimus-eluting stents and paclitaxel-eluting stents, have been compared with bare-metal stents (BMS) in the clinical setting of ST-segment elevation myocardial infarction (STEMI) in several randomized controlled trials and consistently showed a reduction in major adverse cardiac events mainly related to a lower risk of repeat revascularization procedures (1–6).

Notwithstanding, concerns regarding the safety of DES in STEMI patients have been repeatedly raised: pathological analysis of autopsy specimens have revealed more inflammation, fibrin deposition, and uncovered struts among lesions treated with early generation DES in patients with acute myocardial infarction compared with those with stable lesions, suggesting a differential healing response depending on the underlying plaque morphology (7). Intracoronary in vivo imaging studies have further substantiated these findings, highlighting an impaired healing process of DES implanted in thrombotic compared with stable lesions (8).

Whereas the EXAMINATION trial showed a significant reduction in stent thrombosis with the EES (0.9% vs. 2.5%, p = 0.019), the COMFORTABLE-AMI trial demonstrated a significant reduction in major adverse cardiac events with the BES (4.3% vs. 8.7%, p = 0.004) compared with BMS. Nevertheless, neither of these 2 trials had a sample size sufficiently powered to achieve all the safety and efficacy endpoints.

We sought, therefore, to determine whether the benefits of newer DES translate into improved safety compared with BMS among patients with STEMI in an appropriately powered patient population.

Methods

Patient population

We performed a patient-level pooled analysis of the 2 largest multicenter, randomized clinical trials comparing newer-generation DES, with either durable or biodegradable polymer, with BMS (Multilink Vision, Abbott, Santa Clara, California; the Gazelle stent, Biosensors Europe SA, Morges, Switzerland) in STEMI: the EXAMINATION and the COMFORTABLE-AMI trials. Detailed descriptions relating to the design of the 2 trials were reported elsewhere (12,13).

Procedural medications

During the procedure, all patients received unfractionated heparin or bivalirudin, whereas the use of glycoprotein IIb/IIIa antagonists was left at the discretion of the operators. In the EXAMINATION trial, all patients received aspirin (loading dose of 250 to 500 mg and maintenance dose of 100 mg/day) and clopidogrel (loading dose of at least 300 mg and maintenance dose of 75 mg/day). Neither prasugrel nor ticagrelol was approved during the recruitment period. In the COMFORTABLE-AMI, in the centers where prasugrel was available, an initial dose of 60 mg (including patients pre-loaded with clopidogrel) was administered followed by a daily dose of 10 mg. If prasugrel was not available or contraindicated, clopidogrel was administered at a loading dose of 600 mg, followed by a dose of 75 mg twice daily for 7 days, and a maintenance dose of 75 mg once daily thereafter. Dual antiplatelet therapy was prescribed in both trials for at least 1 year in all patients.

Endpoints and definitions

Pre-specified endpoints of this analysis were the device-oriented composite endpoint (DOCE) of cardiac death, target vessel reinfarction and ischemia-driven target lesion revascularization, and the patient-oriented endpoint (POCE) of all-cause death, any myocardial infarction, and any revascularization.

Cardiac death was defined as death because of immediate cardiac causes or complications related to the procedure, as well as any death in which a cardiac cause could not be excluded. Myocardial infarction was defined according to the World Health Organization extended definition (14). Target lesion revascularization was defined as any clinically indicated repeat revascularization (percutaneous or surgical) of the target lesions. Additional endpoints analyzed were the single components of the above-mentioned endpoints. Stent thrombosis was defined according to the Academic Research Consortium criteria (15).

Both trials used identical endpoint definitions, and the chairman of the clinical event committee was the same, ensuring a similar event adjudication process. All the endpoints were evaluated at 1-year follow-up.

Statistical analysis

Continuous data are presented as mean ± SD or median (interquartile range). Categorical data are presented as count and percentage. Comparison between groups was done by a Student t test or chi-square test, as appropriate. Meta-analysis was performed on individual patient data according to intention to treat. Random-effects models were used to assess differences in clinical outcomes between newer generation DES and BMS for the pre-specified DOCE of cardiac death, target-vessel infarction, and target-lesion revascularization and the POCE of all-cause death, any infarction, and any revascularization at 1 year. A 2-sided p value <0.05 was considered as statistically significant. Statistical analysis was performed using the STATA software version 12.1 (StataCorp, College Station, Texas).

Results

Patient population

A total of 2,665 patients were included in the present analysis; the EXAMINATION trial randomly (1:1) assigned 1,504 patients to treatment with EES or BMS, and the COMFORTABLE-AMI trial randomly (1:1) assigned 1,161 patients to treatment with BES or BMS. All patients were stratified according to the type of stent implanted at the index procedure: 1,326 patients received a newer-generation DES with either durable or degradable polymer, whereas the remaining 1,329 patients received a BMS.

Table 1 summarizes the baseline clinical characteristics of the 2 groups. Male sex and hypercholesterolemia tended to be higher in the DES compared with the BMS group. No other differences in clinical or procedural characteristics were observed. Table 2 shows the medication used during the procedure, at discharge, and at follow-up: no differences were found between the 2 groups up to 30-day follow-up. Of note is that at 1 year, dual antiplatelet therapy was frequently used in DES compared with BMS group (93.4% vs. 88.2%, p < 0.001).

Kaplan-Meier curves for the patient-oriented composite endpoint (A) and its individual component, all cause-death (B), any infarction (C), and any revascularization (D) in each of the stent groups. Abbreviations as in Figure 1.

Kaplan-Meier curves for the device-oriented composite endpoint (A) and its individual component, cardiac death (B), target vessel infarction (C), and ischemia-driven target lesion revascularization (D) in each of the stent groups. Abbreviations as in Figure 1.

Forrest plot with hazard ratios of revascularization and stent thrombosis according to their association with target vessel reinfarction for the 2 stent groups. A single outcome is considered associated if it occurred in the −7 to + 7 days from the target vessel reinfarction. Abbreviations as in Figure 1.

The risk of either definite or definite/probable stent thrombosis was lower among patients treated with DES than BMS (HR: 0.35; 95% CI: 0.16 to 0.75; p < 0.01; HR: 0.53; 95% CI: 0.29 to 0.95; p = 0.03, respectively) (Fig. 5). The benefit was particularly evident within the first 30 days after implantation (Table 3).

The benefit in terms of the primary endpoint of DES over BMS was consistent across stratified analyses including body mass index, left anterior descending artery, Thrombolysis In Myocardial Infarction flow, thrombus aspiration, multivessel treatment, lesion length, and vessel diameter. An interaction with stent type was found for age (older than 65 vs. younger than 65 years of age), whereas a tendency for association was observed for diabetes in the DOCE. Interestingly, for definite/probable stent thrombosis, an association with stent type was found with diabetes (Online Figs. 1 to 3).

Discussion

This pooled analysis shows that new-generation DES, with either durable or biodegradable polymer, improve safety and efficacy compared with BMS in appropriately powered STEMI populations.

Early generation DES have been associated with a reduced risk of restenosis compared with BMS (16,17). For this reason, they have quickly replaced BMS for many clinical indications and are progressively used in more complex coronary lesion subsets including off-label settings (18,19). However, the early enthusiasm was dampened by concerns related to the safety profile of DES. In particular, STEMI has been identified as an independent predictor of stent thrombosis after DES implantation (20). It was therefore postulated that although early generation DES were associated with a lower risk of repeat revascularization, this benefit was offset by an increased risk of very late (>1 year) stent thrombosis (18,19,21–23).

Biodegradable polymer DES and DES with more biocompatible durable polymers have been developed with the aim to reduce these adverse effects, related to the persistence of a durable polymer or to a nonbiocompatible durable polymer in the arterial wall (24–26). Recent experimental data indicate a lower thrombogenicity of these DES compared with BMS, suggesting a possible thromboresistant effect of polymer coatings during the early period (27). This may be particularly important in patients with STEMI who carry a higher baseline risk of early stent thrombosis because of a large thrombus burden (28) and increased platelet activation (29). In particular, the thromboresistance of biodegradable polymer-based stents may be related to the presence of biolimus A9, which is the limus analogue with the highest lipophilicity used for DES (9). As the acute coronary lesions predominantly consist of lipid-rich, ruptured plaques with large necrotic cores (30), it may be hypothesized that the increased lipophilicity of biolimus A9 may provide a more rapid and homogeneous drug distribution, potentially leading to a more potent anti-inflammatory and antithrombotic local effects. This hypothesis requires, however, validation in dedicated studies. In addition, the safety profile of these newer-generation DES appears to go beyond 1 year, with a very low rate of stent thrombosis at long-term follow-up (31–33).

The EXAMINATION and COMFORTABLE-AMI trials recently individually tested the safety and efficacy of newer generation DES compared with BMS in STEMI at 1 year of follow-up. However, the power of the individual trials to detect differences in rarely occurring adverse safety endpoints, such as stent thrombosis, was inadequate and one of the reasons to undertake the present analysis. The recently published PROTECT trial is to date the first study designed to detect differences in stent thrombosis between zotarolimus-eluting and sirolimus-eluting stents. However, the trial failed to show differences in terms of the safety endpoint despite a large patient population, which may have been related at least in part to the inclusion of lower-risk patients. Thus, only 9% of patients presented with STEMI, the clinical condition with the highest risk of stent thrombosis and ischemic endpoints (34).

Our meta-analysis shows in an appropriately powered STEMI population that second-generation DES are safe and efficacious compared with BMS in terms of a reduced rate of either device- and patient-oriented endpoints or stent thrombosis during the first year of follow-up. The findings of the current analysis may be regarded as novel and important for at least 2 reasons.

First, with respect to safety, our findings show for the first time a significant and clinically important risk reduction for definite stent thrombosis in favor of newer-generation DES compared with BMS during the first year after stent implantation in a thrombotic milieu such as STEMI. This observation corroborates the above-mentioned experimental and clinical data suggesting a thromboresistant role of the respective polymer-drug combination (27,33).

Second, the target vessel myocardial infarction was less frequent with newer-generation DES than BMS. This difference in safety was not observed in previous randomized trials comparing early generation DES with BMS among patients with STEMI, (1–3,5) but is consistent with the findings of a recent meta-analysis reporting a lower risk of reinfarction during the first year (35). It is interesting to note that a reduction in acute/subacute stent thrombosis was able to reduce target vessel reinfarction but not cardiac mortality. Although the former is strictly dependent on the type of stent implanted, the latter is multifactorial in a STEMI population.

Taken together, these findings may be regarded as an important step to change the treatment paradigm of STEMI patients, suggesting not only a more effective but also safer outcome after DES compared with BMS implantation.

It is unclear whether our results reflect a lack of benefit in diabetic patients. We are unaware of biological mechanisms that might explain interactions with diabetes, and in view of the lack of mechanisms and the large number of stratified analyses, chance should also be considered as an explanation of our findings.

Study limitations

First, this was not a randomized clinical trial, but a pooled analysis of individual patient data from 2 different randomized clinical trials. However, the trials primarily intended to investigate newer-generation DES compared with BMS, consistent with the aim of the present analysis. Moreover, our analysis showed no evidence of heterogeneity across the trials, and pooled individual data revealed no significant and clinically important differences between the 2 groups compared at baseline.

Longer follow-up is needed to confirm that the safety profile, achieved during the first year after implantation, is sustained with persistence of the antirestenotic efficacy and without an increase in very late stent thrombosis. However, in previous studies and meta-analyses BES and EES have been shown to reduce the risk of stent thrombosis beyond 1 year compared, for example, with early generation sirolimus-eluting stents, providing support for the improved long-term biocompatibility of newer-generation DES (31,32).

Conclusions

In patients with STEMI, newer-generation DES improved safety and efficacy compared with BMS throughout 1 year. It remains to be determined whether these differences in favor of newer-generation DES continue during long-term follow-up.

Appendix

Appendix

For supplemental material, please see the online version of this article.

Footnotes

Dr. Sabate is a consultant to Medtronic and Abbott Vascular. Dr. Tüller has received travel grants by Biosensors, Biotronik, Abbott Vascular, and Terumo. Dr. von Birgelen is a consultant to and has received lecture fees or travel expenses from Abbott Vascular, Boston Scientific, and Medtronic; has received lecture fees from Biotronik and Merck; and his institution has received research grants from Abbott Vascular, Biotronik, Boston Scientific, and Medtronic. Dr. Roffi has received research/institutional grants from Abbott Vascular, Boston Scientific, Biosensor, and Medtronic; and is a consultant to Eli Lilly and Daiichi Sankyo. Dr. Juni is an unpaid member of steering group or executive committee of trials funded by Abbott Vascular, Biosensors, Medtronic, and St. Jude Medical. Dr. Windecker is a consultant for Cordis, Medtronic, and St. Jude. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

(2008) Comparison of angioplasty with infusion of tirofiban or abciximab and with implantation of sirolimus-eluting or uncoated stents for acute myocardial infarction: the MULTISTRATEGY randomized trial. JAMA299:1788–1799.